مقالات پذیرفته شده در هشتمین کنگره بین المللی زیست پزشکی
Exploring common and distinctive causes of idiopathic and familial dilated cardiomyopathies via bioinformatic analysis
Exploring common and distinctive causes of idiopathic and familial dilated cardiomyopathies via bioinformatic analysis
Behdokht Fathi Dizaji,1,*
1. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Introduction: Dilated cardiomyopathy (DCM) is a cardiac disorder that leads to the enlargement of left/both ventricles and systolic dysfunction which may contribute to heart failure. The causes of DCM include metabolic, inflammation, infection, neuromuscular disease, tachyarrhythmia, toxins, pregnancy, autoimmune system dysfunction, genetics, and idiopathic. In Patients with idiopathic DCM, the precise etiology of the disease is not clarified, but its familial subtype has a genetic basis. In this study transcriptome data of idiopathic and familial DCM patients were analyzed to identify possible common and distinct genetic and molecular events in these conditions.
Methods: Left ventricular gene expression data of DCM patients and healthy donors (GSE1145) was downloaded from (GEO) database (https:// www. ncbi. nlm. nih. gov/). Differentially expressed genes (DEGs) were identified utilizing (TAC) 4.0 software with false discovery rate (FDR) ≤ 0.05 and log2fold change: > 2 or < -2. The protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, to recognize hub genes. Gephi software was utilized to create functional modules. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology (GO), and DisGeNET enrichment analysis were conducted (P <0.05) to scrutinize the biological functions of DEGs.
Results: A total of 243 DEGs were identified with 154 upregulated and 89 downregulated genes in idiopathic DCM. In familial DCM, 282 DEGs including, 199 upregulated and 83 down-regulated genes were recognized. The PPI network analysis detected 115 proteins, 106 edges for idiopathic, and 186 proteins, 286 edges for familial DCMs. The hub genes with the highest degree in idiopathic DCM were GSPT1, SCN2B, ANOS1, MT-ND6, BTN3A2, BTN3A3, CCNG4, KLHL24, ENPP2, PLA2G2A while, in familial were CCL2, IGF1, LUM, DC163, ASPN, ITGA5, OGN, JAK2, FLNC, SOCS3. Besides, 12 and 15 interconnected modules were recognized in DEGs for idiopathic and familial DCMs respectively. In idiopathic DCM the KEGG pathway analysis indicated, DEGs were enriched in Type I diabetes mellitus, Th1 and Th2 cell differentiation, Hematopoietic cell lineage, dilated cardiomyopathy, etc. In familial DCM, influenza A, type I diabetes mellitus, etc. enriched. Both diseases share many pathways, such as Th1 and Th2 cell differentiation, viral myocarditis, hematopoietic cell lineage, etc. The mainly enriched Go biological processes in idiopathic DCM encompassed: myotube Cell development, positive regulation of cell-substrate adhesion, extracellular matrix organization, and for familial DCM were: immunoglobulin mediated immune response, MHC Class II protein complex assembly, peptide antigen assembly. Nevertheless, both entities share myotube Cell development, muscle Contraction, systemic arterial blood pressure, regulation of potassium Ion export across plasma membrane, and myotube differentiation.
The mainly enriched (GO) molecular functions in idiopathic DCM included ciliary neurotrophic factor receptor binding and cytokine Receptor Binding. In familial DCM MHC Class II Protein Complex Binding and MHC Class II Receptor Activity enriched. In addition, enrichment analysis across important modules was assessed. KEGG pathways enrichment analysis of disease modules demonstrated module 0 of idiopathic DCM was extremely similar to module 1 of familial DCM. Both are involved in amino acid and protein metabolism, however module 1 was also enriched in cancer-related pathways. Enrichment analysis of these modules in DisGeNET showed that both retrieve very similar illnesses, Marinesco-Sjogren syndrome, Oncogenic osteomalacia, Heart failure, etc. Moreover, module 5 of idiopathic DCM was very similar to module 3 of familial DCM which enriched the immune system, infections, etc. Nevertheless, more immune pathways were influenced by module 3. It is also specified in dilated cardiomyopathy, p53 signaling pathway, PI3K-Akt signaling pathway. Therefore, the disease list for module 3 of familial DCM was longer in DisGeNET. Both modules enriched in vascular diseases, myocardial infarction, coronary Arteriosclerosis. The main KEGG-enriched terms were identical in module 9 of idiopathic and module 8 of familial DCMs including cGMP-PKG signaling pathway and Cardiac muscle contraction. In both DCMs main enriched diseases were muscular dystrophies, Limb-Girdle, and Cardiomyopathies. Module 10 of familial DCM indicated unique characteristics. DisGeNET enrichment analysis showed affective Disorders Psychotic, Completed Suicide, and child abuse behavior. It is well-documented that there are strong connections between heart disease and mental illness.
Conclusion: Dilated cardiomyopathy is a genetically and clinically heterogeneous disorder. The exact etiology of idiopathic DMC has not been defined however its familial subtype has a genetic base. This bioinformatic analysis revealed that they have interweaved causes and their distinctive pathophysiology may be distinguished by meta-analysis methods.